Antimicrobial resistance threatens the prevention and treatment of an ever-increasing range of infections caused by bacteria, parasites, viruses, and fungi. An increasing number of governments around the world are devoting efforts to this problem, which is so serious that it threatens the achievements of modern medicine. Far from being an apocalyptic fantasy, a post-antibiotic era in which common infections and minor injuries can kill is a real possibility for the 21st century. A recent WHO report makes a clear case that resistance to common bacteria has reached alarming levels in many parts of the world, and that in some settings few, if any, of the available treatment options remain effective for common infections. Another important finding of the report is that surveillance of antibacterial resistance is neither coordinated nor harmonized and there are many gaps in information regarding bacteria of major public health importance.[1]
The intensive use of antibiotics for the treatment of numerous bacterial infections is one of the biggest healthcare advances in modern times. Nevertheless, their widespread use has led to an increasing number of antibiotic-resistant bacteria.[2] In particular, the emergence of Gram-negative multidrug-resistant (MDR) bacteria, such as Pseudomonas aeruginosa and Klebsiella pneumoniae, has prompted efforts to develop new classes of antibiotics and chemosensitizers (molecules to promote an increase in the internal antibiotic concentration in resistant strains). Thus, diseases caused by MDR Gram-negative bacteria are increasing worldwide,[3,{circumflex over (0)}4] and the emergence of pan drug-resistant (PDR) bacteria (resistant to all classes of antibiotics and to quaternary ammonium disinfectants)[5] appears to have reached a point of no retum.[6,7] A great concern has been noticed in the medical community, as numerous recent clinical reports have confirmed that Gram-negative bacteria have developed resistance to polymyxins, the last efficient therapy against PDR Gram-negative bacteria.[8-10]
An appealing target is the unique structure of the bacterial membrane, which is highly conserved among most species of Gram-negative bacteria, and forms an effective barrier to many types of antibiotics.[11] Indeed, the acquisition of resistance to membrane-active antibiotics has likely required major changes in membrane structure. Ironically, modifications to the bacterial membrane to escape membrane-targeting antibiotics might increase the permeability of the barrier and actually increase the susceptibility of the bacteria to hydrophobic antibiotics.
It is well established that most immune responses to Gram-negative bacteria involve recognition of lipopolysaccharides (LPS) and their lipid-A anchors, which constitute the major components of the outer membrane.[12-17] The permeability barrier of the outer membrane is due to the cross-bridging electrostatic interactions between lipid-A molecules and divalent cations such as calcium or magnesium.[12] It was speculated that cationic peptides[18] and polyamines[19] could out-compete these divalent cations for their membrane binding sites and disrupt the outer membrane organization, thereby increasing permeability. Because of the promising applications of polyamine derivatives in medicine,[20-22] a series of hydrophobic polyamine derivatives have been evaluated for their ability to target the membrane stability of Gram-negative bacteria and increase the sensitivity of these bacteria to known antibiotics.